Journal News

How an oral antiviral drug confuses the replication machinery of SARS-CoV-2

Gillian Rutherford
By Gillian Rutherford
Aug. 26, 2021

A University of Alberta virology lab has uncovered how an oral antiviral drug works to attack the SARS-CoV-2 virus. The findings were published recently in the Journal of Biological Chemistry.

Antiviral-400x336.jpg
Matthias Götte
This mutagenesis model of molnupiravir shows SARS-CoV-2 polymerase
(oval)–mediated nucleotide incorporation into the RNA primer
(grey circles)/template (white circles). Plus and minus signs indicate
RNA sense. A, C, G and U refer to natural nucleotide bases, and M
refers to the active forms of molnupiravir. Three small circles indicate
the triphosphate form of nucleotides. (1) Molnupiravir competes with CTP
for incorporation during synthesis of the negative RNA strand
(copy of the genome). (2) When embedded in the template, molnupiravir
base-pairs with either ATP or GTP. (3) Incorporation of ATP results
in mutagenesis. (4) The mutation is fixed as RNA synthesis continues.
The boxed information provides a summary of events that lead to drug-induced
G to A and C to U transition mutations.

The researchers demonstrated the underlying mechanism of action by which the antiviral drug molnupiravir changes the viral genome, a process known as excessive mutagenesis or error catastrophe.

Matthias Götte is a professor and chair of the medical microbiology and immunology department in the university’s Faculty of Medicine & Dentistry and a member of the Li Ka Shing Institute of Virology. “The polymerase, or replication engine of the virus, mistakes molnupiravir molecules for the natural building blocks required for viral genome replication and mixes them in,” Gotte said. “It causes the polymerase to make sloppy copies — nonsense genomes that are useless and not viable.”

 In clinical trials for efficacy, molnupiravir eliminated SARS-CoV-2 infectivity in newly diagnosed patients after five days of treatment. The drug is taken as a pill, making it much easier to administer than other approved treatments such as remdesivir or monoclonal antibodies, which must be given intravenously.”

“Our work to demonstrate that the effect of the drug is indeed mediated by the viral polymerase is reassuring, because if the drug somehow generates mistakes in the virus and you don’t know how it happens, there could be other mechanisms at work that could also harm the cell. Still, the safety of the drug for COVID-19 patients remains to be evaluated and monitored.”

The ongoing hunt for a weapon against pandemics

The active form of molnupiravir first was identified as a broad-spectrum antiviral at Emory University in Atlanta, Georgia. In 2003, it was developed as a treatment for chronic hepatitis C, but it was dropped due to possible side effects associated with long-term use. The drug then was developed as an influenza antiviral, because the course of treatment for flu is much shorter. The focus of testing switched to SARS-CoV-2 after the COVID-19 pandemic emerged. The drug now is being developed in partnership by Merck and Ridgeback Biotherapeutics.

Merck has made deals with five generic drugmakers in India to make molnupiravir, and at least one of them has applied for approval to use it on an emergency basis, as at least 350,000 new infections are diagnosed in that country every day and vaccination levels are low.

Götte and his team previously uncovered the mechanisms of action for remdesivir, a now-approved treatment that inhibits replication of the SARS-CoV-2 virus, and baloxavir, an influenza drug. 

Next, they will test molnupiravir’s mechanism of action against the polymerases of some of the other viruses the World Health Organization has identified as having high epidemic potential.

“All are recognized as emerging pathogens where we need to develop countermeasures,” Götte said. “We need to be prepared with broad-spectrum antivirals that can serve as a first line of defense.

“Even once vaccines are developed, we can’t get them into all the arms at once,” he said. “To really fight outbreaks and epidemics, one tool is unlikely to be sufficient.”

Enjoy reading ASBMB Today?

Become a member to receive the print edition monthly and the digital edition weekly.

Learn more
Gillian Rutherford
Gillian Rutherford

Gillian Rutherford is a communications advisor for the University of Alberta.

Get the latest from ASBMB Today

Enter your email address, and we’ll send you a weekly email with recent articles, interviews and more.

Latest in Science

Science highlights or most popular articles

Bertrand Coste and the pressure receptor
Feature

Bertrand Coste and the pressure receptor

Jan. 27, 2022

“It was almost one of those ‘I can’t believe you’re doing this’ kind of projects.” The search for a protein that senses pressure. Part of a series on the 2021 Nobel Prize in physiology or medicine.

David McKemy and the cold receptor
Feature

David McKemy and the cold receptor

Jan. 26, 2022

“This is the nature of doing bench work. We all go through those periods when stuff’s not working.” How persistence unlocked the cold-sensitive receptor TRPM8. Part of a series on the 2021 Nobel Prize in physiology or medicine.

How the Julius lab found that an ion channel senses heat
Feature

How the Julius lab found that an ion channel senses heat

Jan. 25, 2022

“Holy cow, this is why hot peppers are hot.” How researchers established that the capsaicin receptor also recognizes heat. Part of a series on the 2021 Nobel Prize in physiology or medicine.

Michael Caterina and the capsaicin receptor
Feature

Michael Caterina and the capsaicin receptor

Jan. 24, 2022

Being scooped left a postdoc with a toolkit for hunting receptors — and a daring new project. First in a series on the 2021 Nobel Prize in physiology or medicine.

Genetic analysis hints at why COVID-19 can mess with smell
News

Genetic analysis hints at why COVID-19 can mess with smell

Jan. 23, 2022

People with variants near smell-related genes may have a higher risk of losing smell or taste.

The coronavirus may cause fat cells to miscommunicate, leading to diabetes
News

The coronavirus may cause fat cells to miscommunicate, leading to diabetes

Jan. 22, 2022

COVID-19 patients with high blood sugar had low levels of a hormone made by fat.